Diabetes effects over 16 million Americans. The World Health Organization indicates that diabetes afflicts 120 million people worldwide, and estimates that this number will increase to 300 million by the year 2025. Diabetics are faced with numerous complications including kidney failure, non-traumatic amputations, an increase in the incidence of heart attack or stroke, nerve damage, and loss of vision. Diabetic retinopathy is a form of visual impairment suffered by diabetics.
In particular, diabetic retinopathy is responsible for 13.1% and 18.2% newly reported cases of blindness for men and women, respectively. Kohner E. M., et al. Diabetic Retinopathy Metabolism, 25:1985-1102 (1975). The prevalence of blind diabetics in the population is about 100 people per million. Id.
Less than optimal methods of treatment for diabetic retinopathy exist. For example, laser treatment may be used to slow the progression of edema, but cannot be used to reverse it. Accordingly, a need exists to develop effective methods of treatment to reduce or impede vision loss and/or diabetic retinopathy.
The present invention relates to methods for inhibiting the binding of a leukocyte to an endothelial cell or another leukocyte, more specifically, in the retinal vasculature and/or capillaries. The present invention pertains to methods of treating (e.g., reducing or preventing) retinal injury in a mammal (e.g., patient) wherein the injury involves retinal edema or retinal ischemia, comprising administering a compound that inhibits the binding of a leukocyte to endothelium or to another leukocyte wherein a reduction in edema (e.g., vascular leakage) or ischemia (e.g., non-perfusion) occurs. The compound comprises an integrin antagonist (e.g., lymphocyte function associated molecule-1 (LFA-1), MAC-1 or p150,95), a selectin (e.g., P-selectin, E-selectin and L-selectin) antagonist, an adhesion molecule antagonist (e.g., Intercellular Adhesion Molecule (ICAM)-1, ICAM-2, ICAM-3 or Vascular Cell Adhesion Molecule (VCAM)), or a leukocyte adhesion inducing cytokine antagonist (e.g., Tumor Neucrosis Factor-xcex1 (TNF-xcex1) and Interleukin-1xcex2 (IL-1xcex2)). The antagonist can be administered with or without a carrier (e.g., pharmaceutically acceptable carrier).
In particular, the invention pertains to methods of treating or preventing retinal injury in a patient comprising administering an intercellular adhesion molecule antagonist. The antagonist can be administered in a carrier (e.g., a pharmaceutically acceptable carrier). The antagonist for intercellular adhesion molecule can be a VCAM, ICAM-2 or ICAM-3 antagonist or, preferably, an ICAM-1 antagonist. In particular, the antagonist can be an antibody or an antibody fragment which is specific for ICAM-1, or an antisense molecule that hybridizes to the nucleic acid sequence which encodes ICAM-1.
The invention also pertains to a method of treating a patient having retinopathy or at risk for retinopathy (e.g., diabetic retinopathy) comprising administering an antagonist (e.g., ICAM-1, ICAM-2 or ICAM-3), as described herein. The antagonist can optionally be administered in a suitable carrier (e.g., pharmnaceutically acceptable carrier). Administration of this antagonist results in a decrease in retinal ischemia and/or retinal edema. Preferably, a decrease in ischemia occurs by at least about 10%, and more preferably, by about 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% (e.g., between 10% and 90%). A decrease in edema can occur by at least about 50%, 60%, 70%, 80%, 90% or preferably, by about 95% (e.g., between 50% and 95%). Accordingly, the claimed invention also relates to methods for treating or preventing retinal edema and/or retinal ischemia comprising administering an ICAM antagonist (e.g., ICAM-1), wherein a decrease in the edema and/or ischemia occurs.
The present invention also relates to methods of treating diabetic retinopathy by comprising administering an ICAM-1 antagonist and at least one additional antagonist that inhibits the binding of a leukocyte to an endothelial cell or to another leukocyte. The additional antagonist can be an integrin antagonist, a selectin antagonist, a leukocyte adhesion inducing antagonist, or another adhesion molecule antagonist. The additional antagonist can be another ICAM antagonist (e.g., an antagonist that is specific for a different portion or epitope of the ICAM-1 molecule) or a VCAM antagonist. The types of integrin antagonists, selectin antagonists, and leukocyte adhesion inducing antagonists are described herein.
The invention also encompasses a method of inhibiting leukocyte interaction, comprising contacting a leukocyte, an endothelial cell or a leukocyte adhesion inducing cytokine, with a compound or antagonist, as defined herein. The compound can be an integrin antagonist, a selectin antagonist, an adhesion molecule antagonist or a leukocyte adhesion inducing cytokine antagonist. In particular, the invention relates to a method of inhibiting leukocyte interaction, comprising contacting an endothelial cell with an adhesion molecule antagonist (e.g., ICAM-1 specific antagonist).
Advantages of the present invention include effective treatment for retinopathy, retinal edema, retinal ischemia and other associated disease. Treatment of these diseases and/or conditions have been ineffective until the discovery of the present invention. For the first time, the present invention provides useful methods of treatment which target molecules that are involved in these diseases.